Intervertebral disc regeneration: From the degenerative cascade to molecular therapy and tissue engineering

Journal of Tissue Engineering and Regenerative Medicine

Volumn 9, Issue 6, 2015, Pages 679-690

  Vadalà, Gianluca ^a   Russo, Fabrizio ^a   Di Martino, Alberto ^a   Denaro, Vincenzo ^a  

^a UNIVERSITY CAMPUS BIO MEDICO   (Italy)

Author keywords

Disc degeneration; Gene therapy; Growth factors; Intervertebral disc; Stem cells; Tissue engineering

Indexed keywords

CELL ENGINEERING; CYTOLOGY; GENE THERAPY; TISSUE; TISSUE REGENERATION;

DISC DEGENERATION; GROWTH FACTOR; INDUSTRIALIZED COUNTRIES; INTER-VERTEBRAL DISC DEGENERATION; INTERVERTEBRAL DISK; LOWER BACK PAIN; MOLECULAR THERAPY; STEM-CELL; TISSUES ENGINEERINGS; WORKING POPULATION;

STEM CELLS;

ADENOVIRUS VECTOR; AGGRECAN; BIOPOLYMER; BONE MORPHOGENETIC PROTEIN 2; EPIDERMAL GROWTH FACTOR; FIBROBLAST GROWTH FACTOR 2; GROWTH DIFFERENTIATION FACTOR 5; OSTEOGENIC PROTEIN 1; PARVOVIRUS VECTOR; RECOMBINANT GROWTH FACTOR; SOMATOMEDIN C; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TRANSCRIPTION FACTOR SOX9; TRANSFORMING GROWTH FACTOR BETA1; TRANSFORMING GROWTH FACTOR BETA3;

ANNULUS FIBROSUS; COLLAGEN SYNTHESIS; EXTRACELLULAR MATRIX; GENE THERAPY; GENETIC POLYMORPHISM; HUMAN; HYDROGEL; INTERVERTEBRAL DISK; INTERVERTEBRAL DISK DEGENERATION; INTERVERTEBRAL DISK HERNIA; LOW BACK PAIN; MESENCHYMAL STEM CELL TRANSPLANTATION; MOLECULAR THERAPY; MUSCULOSKELETAL DISEASE; NONHUMAN; NUCLEUS PULPOSUS; POLYMERIZATION; PRIORITY JOURNAL; PROTEOGLYCAN SYNTHESIS; REVIEW; THROMBOCYTE RICH PLASMA; TISSUE ENGINEERING; TISSUE REGENERATION; TISSUE REPAIR; TISSUE SCAFFOLD; WATER CONTENT; ANIMAL; CLINICAL TRIAL (TOPIC); INTERVERTEBRAL DISC DEGENERATION; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PATHOPHYSIOLOGY; PROCEDURES; REGENERATION;

ANIMALS; CLINICAL TRIALS AS TOPIC; HUMANS; INTERVERTEBRAL DISC; INTERVERTEBRAL DISC DEGENERATION; MOLECULAR TARGETED THERAPY; REGENERATION; TISSUE ENGINEERING;

EID: 84931003903     PISSN: 19326254     EISSN: 19327005     Source Type: Journal    
DOI: 10.1002/term.1719     Document Type: Review

References (136)

1. Adams MA, Roughley PJ. 2006; What is intervertebral disc degeneration, and what causes it? Spine (Phila PA 1976) 31: 2151-2161.
2. Afione SA, Wang J, Walsh S et al. 1999; Delayed expression of adeno-associated virus vector DNA. Intervirology 42: 213-220.
3. Akeda K, An HS, Pichika R et al. 2006; Platelet-rich plasma (PRP) stimulates the extracellular matrix metabolism of porcine nucleus pulposus and annulus fibrosus cells cultured in alginate beads. Spine (Phila Pa 1976) 31: 959-966.
4. Alini M, Li W, Markovic P et al. 2003; The potential and limitations of a cell-seeded collagen/hyaluronan scaffold to engineer an intervertebral disc-like matrix. Spine (Phila Pa 1976) 28: 446-454; discussion, 453.
5. Alini M, Eisenstein SM, Ito K et al. 2008; Are animal models useful for studying human disc disorders/degeneration? Eur Spine J 17: 2-19.
6. Annunen S, Paassilta P, Lohiniva J et al. 1999; An allele of COL9A2 associated with intervertebral disc disease. Science 285: 409-412.
7. Baer AE, Wang JY, Kraus VB et al. 2001; Collagen gene expression and mechanical properties of intervertebral disc cell-alginate cultures. J Orthop Res 19: 2-10.
8. Bartels EM, Fairbank JC, Winlove CP et al. 1998; Oxygen and lactate concentrations measured in vivo in the intervertebral discs of patients with scoliosis and back pain. Spine (Phila Pa 1976) 23: 1-7; discussion, 8.
9. Battie MC, Videman T, Parent E. 2004; Lumbar disc degeneration: epidemiology and genetic influences. Spine (Phila Pa 1976) 29: 2679-2690.
10. Benneker LM, Heini PF, Alini M et al. 2005; 2004 Young Investigator Award Winner: vertebral endplate marrow contact channel occlusions and intervertebral disc degeneration. Spine (Phila Pa 1976) 30: 167-173.
11. Bertram H, Kroeber M, Wang H et al. 2005; Matrix-assisted cell transfer for intervertebral disc cell therapy. Biochem Biophys Res Commun 331: 1185-1192.
12. Blau HM, Brazelton TR, Weimann JM. 2001; The evolving concept of a stem cell: entity or function? Cell 105: 829-841.
13. Boden SD, Liu Y, Hair GA et al. 1998; LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation. Endocrinology 139: 5125-5134.
14. Boni M, Denaro V. 1987; Anatomo-clinical correlations in cervical spondylosis. In Cervical Spine I, Kehr P, Weidner A (eds). Springer-Verlag: New York; 3-20.
15. Bowles RD, Williams RM, Zipfel WR et al. 2010; Self-assembly of aligned tissue-engineered annulus fibrosus and intervertebral disc composite via collagen gel contraction. Tissue Eng Part A 16: 1339-1348.
16. Bron JL, Helder MN, Meisel HJ et al. 2009; Repair, regenerative and supportive therapies of the annulus fibrosus: achievements and challenges. Eur Spine J 18: 301-313.
17. Buckwalter JA. 1995; Aging and degeneration of the human intervertebral disc. Spine (Phila Pa 1976) 20: 1307-1314.
18. Cao B, Zheng B, Jankowski RJ et al. 2003; Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat Cell Biol 5: 640-646.
19. Carragee EJ, Don AS, Hurwitz EL et al. 2009; 2009 ISSLS Prize Winner: does discography cause accelerated progression of degeneration changes in the lumbar disc: a ten-year matched cohort study. Spine (Phila Pa 1976) 34: 2338-2345.
20. Chan SC, Gantenbein-Ritter B. 2012; Intervertebral disc regeneration or repair with biomaterials and stem cell therapy - feasible or fiction? Swiss Med Weekly 142: w13598.
21. Chang G, Kim HJ, Kaplan D et al. 2007; Porous silk scaffolds can be used for tissue engineering annulus fibrosus. Eur Spine J 16: 1848-1857.
22. Chang G, Kim HJ, Vunjak-Novakovic G et al. 2010; Enhancing annulus fibrosus tissue formation in porous silk scaffolds. J Biomed Mater Res A 92: 43-51.
23. Chiba K, Andersson GB, Masuda K et al. 1997; Metabolism of the extracellular matrix formed by intervertebral disc cells cultured in alginate. Spine (Phila Pa 1976) 22: 2885-2893.
24. Crevensten G, Walsh AJ, Ananthakrishnan D et al. 2004; Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs. Ann Biomed Eng 32: 430-434.
25. Di Martino A, Vaccaro AR, Lee JY et al. 2005; Nucleus pulposus replacement: basic science and indications for clinical use. Spine (Phila Pa 1976) 30: S16-22.
26. Fassett DR, Kurd MF, Vaccaro AR. 2009; Biologic solutions for degenerative disk disease. J Spinal Disord Tech 22: 297-308.
27. Gruber HE, Hanley EN Jr. 1998; Analysis of aging and degeneration of the human intervertebral disc. Comparison of surgical specimens with normal controls. Spine (Phila Pa 1976) 23: 751-757.
28. Haberstroh K, Enz A, Zenclussen ML et al. 2009; Human intervertebral disc-derived cells are recruited by human serum and form nucleus pulposus-like tissue upon stimulation with TGF-β3 or hyaluronan in vitro. Tissue Cell 41: 414-420.
29. Halloran DO, Grad S, Stoddart M et al. 2008; An injectable cross-linked scaffold for nucleus pulposus regeneration. Biomaterials 29: 438-447.
30. Hastreiter D, Ozuna RM, Spector M. 2001; Regional variations in certain cellular characteristics in human lumbar intervertebral discs, including the presence of α-smooth muscle actin. J Orthop Res 19: 597-604.
31. Hegewald AA, Ringe J, Sittinger M et al. 2008; Regenerative treatment strategies in spinal surgery. Front Biosci 13: 1507-1525.
32. Helen W, Gough JE. 2008; Cell viability, proliferation and extracellular matrix production of human annulus fibrosus cells cultured within PDLLA/bioglass composite foam scaffolds in vitro. Acta Biomater 4: 230-243.
33. Henriksson HB, Svanvik T, Jonsson M et al. 2009; Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine (Phila Pa 1976) 34: 141-148.
34. Hiyama A, Mochida J, Iwashina T et al. 2008a; Transplantation of mesenchymal stem cells in a canine disc degeneration model. J Orthop Res 26: 589-600.
35. Hiyama A, Mochida J, Sakai D. 2008b; Stem cell applications in intervertebral disc repair. Cell Mol Biol (Noisy-le-Grand) 54: 24-32.
36. Holzapfel GA, Schulze-Bauer CA, Feigl G et al. 2005; Single lamellar mechanics of the human lumbar annulus fibrosus. Biomech Modeling Mechanobiol 3: 125-140.
37. Hubert MG, Vadala G, Sowa G et al. 2008; Gene therapy for the treatment of degenerative disk disease. J Am Acad Orthop Surg 16: 312-319.
38. Hunter CJ, Matyas JR, Duncan NA. 2003; The notochordal cell in the nucleus pulposus: a review in the context of tissue engineering. Tissue Eng 9: 667-677.
39. Illien-Junger S, Pattappa G, Peroglio M et al. 2012; Homing of mesenchymal stem cells in induced degenerative intervertebral discs in a whole organ culture system. Spine (Phila Pa 1976) 37: 1865-1873.
40. Kang JD, Stefanovic-Racic M, McIntyre LA et al. 1997; Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine (Phila Pa 1976) 22: 1065-1073.
41. Katz MM, Hargens AR, Garfin SR. 1986; Intervertebral disc nutrition. Diffusion versus convection. Clin Orthop Relat Res 210: 243-245.
42. Kawaguchi Y, Osada R, Kanamori M et al. 1999; Association between an aggrecan gene polymorphism and lumbar disc degeneration. Spine 24: 2456-2460.
43. Kim JH, Deasy BM, Seo HY et al. 2009; Differentiation of intervertebral notochordal cells through live automated cell imaging system in vitro. Spine (Phila Pa 1976) 34: 2486-2493.
44. Le Maitre CL, Freemont AJ, Hoyland JA. 2005; The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther 7: R732-745.
45. Leckie SK, Bechara BP, Hartman RA et al. 2012; Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J 12: 7-20.
46. Lee H, Sowa G, Vo N et al. 2010; Effect of bupivacaine on intervertebral disc cell viability. Spine J 10: 159-166.
47. Lee JY, Qu-Petersen Z, Cao B et al. 2000; Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J Cell Biol 150: 1085-1100.
48. Leone G, Torricelli P, Chiumiento A et al. 2008; Amidic alginate hydrogel for nucleus pulposus replacement. J Biomed Mater Res A 84: 391-401.
49. Leung VY, Tam V, Chan D et al. 2011; Tissue engineering for intervertebral disk degeneration. Orthopedic Clin N Am 42: 575-583, ix.
50. Levicoff EA, Kim JS, Sobajima S et al. 2008; Safety assessment of intradiscal gene therapy II: effect of dosing and vector choice. Spine (Phila Pa 1976) 33: 1509-1516; discussion, 1517.
51. Li J, Yoon ST, Hutton WC. 2004a; Effect of bone morphogenetic protein-2 (BMP-2) on matrix production, other BMPs, and BMP receptors in rat intervertebral disc cells. J Spinal Disord Tech 17: 423-428.
52. Li X, Leo BM, Beck G et al. 2004b; Collagen and proteoglycan abnormalities in the GDF-5-deficient mice and molecular changes when treating disk cells with recombinant growth factor. Spine (Phila Pa 1976) 29: 2229-2234.
53. Li X, Lee JP, Balian G et al. 2005; Modulation of chondrocytic properties of fat-derived mesenchymal cells in co-cultures with nucleus pulposus. Connect Tissue Res 46: 75-82.
54. Liebscher T, Haefeli M, Wuertz K et al. 2011; Age-related variation in cell density of human lumbar intervertebral disc. Spine (Phila Pa 1976) 36: 153-159.
55. Lotz JC, Ulrich JA. 2006; Innervation, inflammation, and hypermobility may characterize pathologic disc degeneration: review of animal model data. J Bone Joint Surg Am 88(suppl 2): 76-82.
56. Lu ZF, Zandieh Doulabi B, Wuisman PI et al. 2007; Differentiation of adipose stem cells by nucleus pulposus cells: configuration effect. Biochem Biophys Res Commun 359: 991-996.
57. Luo X, Pietrobon R, Sun SX et al. 2004; Estimates and patterns of direct health care expenditures among individuals with back pain in the United States. Spine (Phila Pa 1976) 29: 79-86.
58. Masuda K, Oegema TR Jr., An HS. 2004; Growth factors and treatment of intervertebral disc degeneration. Spine (Phila Pa 1976) 29: 2757-2769.
59. Masuda K, Imai Y, Okuma M et al. 2006; Osteogenic protein-1 injection into a degenerated disc induces the restoration of disc height and structural changes in the rabbit annular puncture model. Spine (Phila Pa 1976) 31: 742-754.
60. Masuda K, Lotz JC. 2010; New challenges fo intervertebral disc treatment using regenerative medicine. Tissue Eng Part B Rev 16: 147-158.
61. Mauth C, Bono E, Haas S et al. 2009; Cell-seeded polyurethane-fibrin structures - a possible system for intervertebral disc regeneration. Eur Cell Mater 18: 27-38; discussion, 38-29.
62. Meisel HJ, Ganey T, Hutton WC et al. 2006; Clinical experience in cell-based therapeutics: intervention and outcome. Eur Spine J 15(suppl 3): S397-405.
63. Miyamoto T, Muneta T, Tabuchi T et al. 2011; Intradiscal transplantation of synovial mesenchymal stem cells prevents intervertebral disc degeneration through suppression of matrix metalloproteinase-related genes in nucleus pulposus cells in rabbits. Arthritis Res Ther 12: R206.
64. Mizuno H, Roy AK, Vacanti CA et al. 2004; Tissue-engineered composites of annulus fibrosus and nucleus pulposus for intervertebral disc replacement. Spine (Phila Pa 1976) 29: 1290-1297; discussion, 1297-1298.
65. Moon SH, Nishida K, Gilbertson LG et al. 2008; Biologic response of human intervertebral disc cells to gene therapy cocktail. Spine (Phila Pa 1976) 33: 1850-1855.
66. Mortisen D, Peroglio M, Alini M et al. 2010; Tailoring thermoreversible hyaluronan hydrogels by 'click' chemistry and RAFT polymerization for cell and drug therapy. Biomacromolecules 11: 1261-1272.
67. Mulholland RC. 2008; The myth of lumbar instability: the importance of abnormal loading as a cause of low back pain. Eur Spine J 17: 619-625.
68. Murrell W, Sanford E, Anderberg L et al. 2009; Olfactory stem cells can be induced to express chondrogenic phenotype in a rat intervertebral disc injury model. Spine J 9: 585-594.
69. Nerurkar NL, Baker BM, Sen S et al. 2009; Nanofibrous biologic laminates replicate the form and function of the annulus fibrosus. Nat Mater 8: 986-992.
70. Nesti LJ, Li WJ, Shanti RM et al. 2008; Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. Tissue Eng Part A 14: 1527-1537.
71. Nishida K, Kang JD, Gilbertson LG et al. 1999; Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor-β1 encoding gene. Spine (Phila Pa 1976) 24: 2419-2425.
72. Oguz E, Tsai TT, Di Martino A et al. 2007; Galectin-3 expression in the intervertebral disc: a useful marker of the notochord phenotype? Spine (Phila Pa 1976) 32: 9-16.
73. Orozco L, Soler R, Morera C et al. 2011; Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 15: 822-828.
74. Osada R, Ohshima H, Ishihara H et al. 1996; Autocrine/paracrine mechanism of insulin-like growth factor-1 secretion, and the effect of insulin-like growth factor-1 on proteoglycan synthesis in bovine intervertebral discs. J Orthop Res 14: 690-699.
75. Park SH, Gil ES, Mandal BB et al. 2012; Annulus fibrosus tissue engineering using lamellar silk scaffolds. J Tissue Eng Regen Med Suppl 6: s24-33.
76. Paul R, Haydon RC, Cheng H et al. 2003; Potential use of Sox9 gene therapy for intervertebral degenerative disc disease. Spine (Phila Pa 1976) 28: 755-763.
77. Peroglio M, Grad S, Mortisen D et al. 2011; Injectable thermoreversible hyaluronan-based hydrogels for nucleus pulposus cell encapsulation. Eur Spine J Suppl 6: S839-849.
78. Peroglio M, Grad S, Mortisen D et al. 2012; Injectable thermoreversible hyaluronan-based hydrogels for nucleus pulposus cell encapsulation. Eur Spine J 21(suppl 6): 839-849.
79. Pfeiffer M, Boudriot U, Pfeiffer D et al. 2003; Intradiscal application of hyaluronic acid in the non-human primate lumbar spine: radiological results. Eur Spine J 12: 76-83.
80. Pittenger MF, Mackay AM, Beck SC et al. 1999; Multilineage potential of adult human mesenchymal stem cells. Science 284: 143-147.
81. Revell PA, Damien E, Di Silvio L et al. 2007; Tissue engineered intervertebral disc repair in the pig using injectable polymers. J Mater Sci Mater Med 18: 303-308.
82. Reza AT, Nicoll SB. 2010; Characterization of novel photocrosslinked carboxymethylcellulose hydrogels for encapsulation of nucleus pulposus cells. Acta Biomater 6: 179-186.
83. Richardson SM, Hoyland JA. 2008; Stem cell regeneration of degenerated intervertebral discs: current status. Curr Pain Headache Rep 12: 83-88.
84. Richardson SM, Hoyland JA, Mobasheri R et al. 2010; Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol 222: 23-32.
85. Risbud MV, Albert TJ, Guttapalli A et al. 2004; Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy. Spine (Phila Pa 1976) 29: 2627-2632.
86. Risbud MV, Di Martino A, Guttapalli A et al. 2006; Toward an optimum system for intervertebral disc organ culture: TGF-β3 enhances nucleus pulposus and annulus fibrosus survival and function through modulation of TGF-βR expression and ERK signaling. Spine (Phila Pa 1976) 31: 884-890.
87. Risbud MV, Guttapalli A, Tsai TT et al. 2007; Evidence for skeletal progenitor cells in the degenerate human intervertebral disc. Spine (Phila Pa 1976) 32: 2537-2544.
88. Roberts S, Caterson B, Menage J et al. 2000; Matrix metalloproteinases and aggrecanase: their role in disorders of the human intervertebral disc. Spine (Phila Pa 1976) 25: 3005-3013.
89. Ruan D, Zhang Y, Wang D et al. 2011; Differentiation of human Wharton's jelly cells toward nucleus pulposus-like cells after coculture with nucleus pulposus cells in vitro. Tissue Eng Part A 18: 167-175.
90. Ruan DK, Xin H, Zhang C et al. 2010; Experimental intervertebral disc regeneration with tissue-engineered composite in a canine model. Tissue Eng Part A 16: 2381-2389.
91. Sakai D, Mochida J, Yamamoto Y et al. 2003; Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials 24: 3531-3541.
92. Sakai D, Mochida J, Iwashina T et al. 2005; Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model: potential and limitations for stem cell therapy in disc regeneration. Spine (Phila Pa 1976) 30: 2379-2387.
93. Sakai D, Mochida J, Iwashina T et al. 2006; Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials 27: 335-345.
94. Seki S, Kawaguchi Y, Chiba K et al. 2005; A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet 37: 607-612.
95. Sha'ban M, Kim SH, Idrus RB et al. 2008; Fibrin and poly(lactic-co-glycolic acid) hybrid scaffold promotes early chondrogenesis of articular chondrocytes: an in vitro study. J Orthop Surg Res 3: 17.
96. Shao X, Hunter CJ. 2007; Developing an alginate/chitosan hybrid fiber scaffold for annulus fibrosus cells. J Biomed Mater Res A 82: 701-710.
97. Silva-Correia J, Miranda-Goncalves V, Salgado A et al. 2012; Angiogenic potential of gellan gum-based hydrogels for application in nucleus pulposus regeneration: in vivo study. Tissue Eng Part A 18: 1203-1212.
98. Smith LJ, Nerurkar NL, Choi KS et al. 2011; Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Models Mech 4: 31-41.
99. Sobajima S, Kompel JF, Kim JS et al. 2005a; A slowly progressive and reproducible animal model of intervertebral disc degeneration characterized by MRI, X-ray, and histology. Spine (Phila Pa 1976) 30: 15-24.
100. Sobajima S, Shimer AL, Chadderdon RC et al. 2005b; Quantitative analysis of gene expression in a rabbit model of intervertebral disc degeneration by real-time polymerase chain reaction. Spine J 5: 14-23.
101. Sobajima S, Vadala G, Shimer A et al. 2008; Feasibility of a stem cell therapy for intervertebral disc degeneration. Spine J 8: 888-896.
102. Solovieva S, Kouhia S, Leino-Arjas P et al. 2004, Interleukin 1 polymorphisms and intervertebral disc degeneration. Epidemiology 15: 626-633.
103. Sowa G, Vadala G, Studer R et al. 2008, Characterization of intervertebral disc aging: longitudinal analysis of a rabbit model by magnetic resonance imaging, histology, and gene expression. Spine (Phila Pa 1976) 33: 1821-1828.
104. Sowa G, Westrick E, Pacek C et al. 2011; In vitro and in vivo testing of a novel regulatory system for gene therapy for intervertebral disc degeneration. Spine (Phila Pa 1976) 36: E623-628.
105. Spadaccio C, Rainer A, Trombetta M et al. 2009; Poly-l-lactic acid/hydroxyapatite electrospun nanocomposites induce chondrogenic differentiation of human MSC. Ann Biomed Eng 37: 1376-1389.
106. Studer RK, Aboka AM, Gilbertson LG et al. 2007; p38 MAPK inhibition in nucleus pulposus cells: a potential target for treating intervertebral disc degeneration. Spine (Phila Pa 1976) 32: 2827-2833.
107. Takahashi M, Haro H, Wakabayashi Y et al. 2001; The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene. J Bone Joint Surg Br 83: 491-495.
108. Takegami K, Thonar EJ, An HS et al. 2002; Osteogenic protein-1 enhances matrix replenishment by intervertebral disc cells previously exposed to interleukin-1. Spine (Phila Pa 1976) 27: 1318-1325.
109. Terada N, Hamazaki T, Oka M et al. 2002; Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416: 542-545.
110. Thompson JP, Oegema TR Jr., Bradford DS. 1991; Stimulation of mature canine intervertebral disc by growth factors. Spine (Phila Pa 1976) 16: 253-260.
111. Toma JG, Akhavan M, Fernandes KJ et al. 2001; Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 3: 778-784.
112. Trout JJ, Buckwalter JA, Moore KC et al. 1982; Ultrastructure of the human intervertebral disc. I. Changes in notochordal cells with age. Tissue Cell 14: 359-369.
113. Urban JP, McMullin JF. 1985; Swelling pressure of the inervertebral disc: influence of proteoglycan and collagen contents. Biorheology 22: 145-157.
114. Urban JP, Smith S, Fairbank JC. 2004; Nutrition of the intervertebral disc. Spine (Phila Pa 1976) 29: 2700-2709.
115. Vadala G, Sowa GA, Kang JD. 2007a; Gene therapy for disc degeneration. Expert Opin Biol Ther 7: 185-196.
116. Vadala G, Sowa GA, Smith L et al. 2007b; Regulation of transgene expression using an inducible system for improved safety of intervertebral disc gene therapy. Spine (Phila Pa 1976) 32: 1381-1387.
117. Vadala G, Sobajima S, Lee JY et al. 2008a; In vitro interaction between muscle-derived stem cells and nucleus pulposus cells. Spine J 8: 804-809.
118. Vadala G, Studer RK, Sowa G et al. 2008b; Coculture of bone marrow mesenchymal stem cells and nucleus pulposus cells modulate gene expression profile without cell fusion. Spine (Phila Pa 1976) 33: 870-876.
119. Vadala G, Mozetic P, Rainer A et al. 2012a; Bioactive electrospun scaffold for annulus fibrosus repair and regeneration. Eur Spine J 21(suppl 1): S20-26.
120. Vadala G, Sowa G, Hubert M et al. 2012b; Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med 6: 348-355.
121. Vadalá G, Russo F, Patappa G et al. 2013; The transpedicular approach as an alternative route for intervertebral disc regeneration. Spine (Phila Pa 1976) 38: in press.
122. Videman T, Leppavuori J, Kaprio J et al. 1998; Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine (Phila Pa 1976) 23: 2477-2485.
123. Wallace AL, Wyatt BC, McCarthy ID et al. 1994; Humoral regulation of blood flow in the vertebral endplate. Spine (Phila Pa 1976) 19: 1324-1328.
124. Wallach CJ, Sobajima S, Watanabe Y et al. 2003; Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine (Phila Pa 1976) 28: 2331-2337.
125. Wan Y, Feng G, Shen FH et al. 2007; Novel biodegradable poly(1, 8-octanediol malate) for annulus fibrosus regeneration. Macromol Biosci 7: 1217-1224.
126. Wan Y, Feng G, Shen FH et al. 2008; Biphasic scaffold for annulus fibrosus tissue regeneration. Biomaterials 29: 643-652.
127. Weibrich G, Kleis WK, Hafner G et al. 2002; Growth factor levels in platelet-rich plasma and correlations with donor age, sex, and platelet count. J Craniomaxillofac Surg 30: 97-102.
128. Weiler C, Nerlich AG, Zipperer J et al. 2002; 2002 SSE Award Competition in Basic Science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption. Eur Spine J 11: 308-320.
129. Wilda H, Gough JE. 2006; In vitro studies of annulus fibrosus disc cell attachment, differentiation and matrix production on PDLLA/45S5 bioglass composite films. Biomaterials 27: 5220-5229.
130. Winn SR, Uludag H, Hollinger JO. 1999; Carrier systems for bone morphogenetic proteins. Clin Orthop Relat Res 367 Suppl: S95-106.
131. Wobus AM. 2001; Potential of embryonic stem cells. Mol Aspects Med 22: 149-164.
132. Yamamoto Y, Mochida J, Sakai D et al. 2004; Upregulation of the viability of nucleus pulposus cells by bone marrow-derived stromal cells: significance of direct cell-to-cell contact in coculture system. Spine (Phila Pa 1976) 29: 1508-1514.
133. Yang X, Li X. 2009; Nucleus pulposus tissue engineering: a brief review. Eur Spine J 18: 1564-1572.
134. Zhang Y, Drapeau S, Howard SA et al. 2011; Transplantation of goat bone marrow stromal cells to the degenerating intervertebral disc in a goat disc injury model. Spine (Phila Pa 1976) 36: 372-377.
135. Zobel BB, Vadala G, Del Vescovo R et al. 2012; T1rho magnetic resonance imaging quantification of early lumbar intervertebral disc degeneration in healthy young adults. Spine (Phila Pa 1976) 37: 1224-1230.
136. Zuk PA, Zhu M, Mizuno H et al. 2001; Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7: 211-228.